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Growth Hormone Deficiency, GHD

Growth Hormone Deficiency, GHD

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Growth Hormone Deficiency, GHD

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  1. Growth Hormone Deficiency, GHD

  2. Short stature • Below the 3rd percentile or -2SD than that of his or her peers • Short stature has many causes, the pathologic short stature should be suspected in children who have an abnormal growth velocity or who are significantly short for their family

  3. Growth Hormone Chemistry:191 animo acid,22-KDa protein

  4. To growth of the epiphyseal regions of the long bones, also via induce local IGF-1 production in the epiphyseal plate at the both level of mRNA and protein. • to promote the cell proliferation.

  5. A variety of metabolic effect, such as Anabolic action on protein metabolic, lipolysis, animo acid transport in diaphragm and heart. • “Diabetogenic” action on large GH dose. • The effects in normal aging and catabolic conditions are under investigation.

  6. 下丘脑-GH-IGF轴

  7. Etiology of GH deficiency Genetic forms It can be transmitted as an autosomal recessive, autosomal dominat or X-linked recessive trait. Abnormalities of the genes: GHRH receptor, Pouifi, Prop1, GH1, GH receptor, IGF-1 etc. Acquired forms The GH axis is more susceptible to disruption by acquired conditions that are the other hypothalamic-pituitary axes. Craniopharyngioma, eosinophilic granuloma, tuberculosis, Trauma, radiotherapy for malignancies

  8. Clinical manifestations • Short stature: slow growth in height, • Congenital form: birth length is below the mean, 2-4Sd below the mean by 1 year of age. • Acquired form: normal initially, growth faillure gradually appear and progress • Delayed closure of the epiphyses. • The head is round, the face is short and broad. The neck is short, the voice is high-pitched, the genitals are undeveloped and sexual maturation may be delayed or absent. The scalp hair is fine. • Some with ACTH、TSH、GnRH and ADH deficiency.

  9. Clinical manifestations • Short stature:   blow the 3rd percentile or -2SD than that of his or her peers • slow growth in height

  10. 0-12 months - grows about 25 cm • 1-2 years - grows about 13 cm • 2-3 years - grows about 7cma year, most children will double their birth height by 3-4 years of age • 3 years to puberty - grows about 5cm a year

  11. Abnormal growth velocity 2y(< 7 cm/yr) 4.5-prepuberty(< 5 cm/yr) adolecent(< 6 cm/yr)

  12. Laboratory findings • Definitive diagnosis: GH provocative tests: Insulin 0.05-0.1u/Kg Arginine 0.5g/kg Clonidine 4ug/kg L-dopa 10mg/kg Blood GH test at 0、30、60、90、120min • Peak level less than 10ug: GH deficiency • The frequency of false-negative response to a single testis approximately 20%

  13. Laboratory findings(2) • Additional measurement: IGF-1,IGFBP-3, TSH,T4,ACTH,LHRH. • X ray : delayed bone age • Image examination:Skull study by X ray, CT or MRI to observe the calcification, erosion within or above the sella etc..

  14. body proportion body disproportion Differential diagnosis

  15. body disproportion

  16. body proportion FSS SGA  Turner’ssyndrome

  17. FSS (familial short stature) Short parents Normal birth history and gestational weight Short stature Normal Linear Growth Velocity for age Bone age consistent with chronological age Normal age for the onset of Puberty Absence of organic or psychologic disease

  18. SGA

  19. Turner’sSyndrome affects about 1 in every 2,500 girls Girls with Turner syndrome are usually short in height. Those who aren't treated for short stature reach an average height of about 4 feet 7 inches (1.4 meters) Turner syndrome prevents the ovaries from developing properly, which affects a girl's sexual development and the ability to have children

  20. physical features commonly seen in girls with Turner syndrome are: • a "webbed" neck (extra folds of skin extending from the tops of the shoulders to the sides of the neck) • a low hairline at the back of the neck • drooping of the eyelids • differently shaped ears that are set lower on the sides of the head than usual • abnormal bone development (especially the bones of the hands and elbows) • a larger than usual number of moles on the skin • edema or extra fluid in the hands and feet

  21. 女 13岁 H130cm

  22. Treatment • Treatment should be started as soon as possible to narrow the gap in height between patients and their classmates and to have greatest effect on mature height. • GH replacement:0.1 U/kg/d, it is subcutaneously in six or seven • Therapy should be continuous until near final height is achieved.

  23. Stopping treatment : bone age of greater than 14 yr in girl and greater that 16 yr in boys. Replacement should also be directed at other hormonal deficiencies • TSH deficient subjects: L-T4 • ACTH deficient patients: hydrocortisone • Gonadotropins deficient patients: gonaddal steroids

  24. rhGH is a growth hormone produced by Genentech using recombinant DNA technology. It has the same amino acid sequence as growth hormone produced naturally in the human body.  To avoid tissue atrophy that may result from subcutaneous administration of GH at the same site over a long period of time, the injection site should be rotated.

  25. Congenital Hypothyroidism,CH

  26. Incidence • Thyroid hormone deficiency may: or acquired • Congenital:most cases are hypoplasia or aplasia of the thyroid gland World: 1:3 000~5 000 China: 1:3 200

  27. Thyroid hormone synthesis and metabolism • The thyroid follicle is stimulated by TSH by increase with TSH receptor • Iodine from the circulation is concentrated and rapidly oxidized by peroxidase to iodine • Iodine incorporated into tyrosyl residures on thyroglobuline • Iodothyrosines are couple an ether linkage to form T4 and T3

  28. Physiological of thyroid hormones • Increase oxygen consumption • Stimulate protein synthesis • Influence growth and differentiation • Affect carbohydrate, lipid and vitamine metabolism

  29. Thyroxine and its precursors: Structure & Synthesis Figure: Thyroid hormones are made from tyrosine and iodine

  30. Hypothalamus Anterior pituitary gland Thyroid gland TRH TSH - rT3 T4 T3 Hypothylamic-pitutary-thyroid feedback regulation

  31. Clinical Findings In Newborns and Infants • Absent symptom during the first few weeks of life • A few have birth weight>3.5kg prolongation of physiological icterus, constipation, hoarse cry, feeding or sucking difficulties

  32. sporadic Symptoms and signs

  33. Progress Manifestation • Pulse is slow, heart murnures, cardiomegaly, hypothermia, hypotonia, enlarged tongue, skin cold and dry, umbilical hernia, hair is dry • Mental retardation • growth stunted

  34. Laboratory findings TSH in neonatal screening programs: <10~15 mu/L Normal range for neonate T4 84-210 nmol/l(6.5-16.3ug/dl) FT4 12-28 pmol/l(0.9-2.2ng/dl) TSH 1.7-9.1 mu/L(1.7-9.1 uU/ml)

  35. After delivery, TSH rapidly rise reaching 60~80 uU/ml levels, and then slowly decline over the next few days(5~7d) to <5 uU/ml levels

  36. 99mTc、123I scintigraphy • B ultrasound examination • X ray: retardation of skeletal maturation (bone age)

  37. Treatment Principal • Give thyroxine as early as possible • TSH and FT4 should be monitored and maintained in the normal range • Confirmation of diagnosis may be necessary for some infant to rule out the possibility of transient hypothyroidism at 2~3 years old

  38. Dose of thyroxine(L-T4) ────────────────────── Age μg/day ug/kg/day ────────────────────── 0~6m 25~50 8.5~10 6~12m 50~100 5~8 1~5y 75~100 5~6 6~12y 100~150 4~5 12y to adult 100~200 2~3 ──────────────────────

  39. Precocious Puberty

  40. Puberty vs. pseudopuberty • Puberty - evidence of activation of both hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: pubic hair plus breast development in girls, pubic hair plus testicular enlargement in boys • Pseudopuberty - evidence of activation of only one axis or of an etiological axis other than hypothalamus-pituitary

  41. Early vs. precocious puberty • Precocious: appearance of both pubic hair and genital development in a male < 9 years of age and pubic hair plus breast development in a female < 8 years of age • Early benign: puberty beginning at age 7 years in girls (6-7 in African American) may be benign

  42. Early puberty • Question: does normal puberty begin at the same age range in all ethnic groups? No

  43. Beijing 1963 menarche age 14.5yrs; 1984 12.4yrs; 2004 12.1yrs Shanghai 1978 14.1yrs;1989 12.5yrs • 1993,HongKong:50% menarche age 12.5yrs, 6mon advanced as compared with 30 years ago

  44. North Carolina Study • At age 8 yr, 37.8% of African American, 10.5% of Caucasian girls had stage B2 • At age 7 yr, 15.4% of African American, 5% of Caucasian girls had stage B2 • But mean age of menarche was not accelerated - 12.2 yr in African Americans, 12.9 yr in Caucasians

  45. HYPOTHALAMUS GnRH AND GHRH PITUITARY GROWTH LH & FSH HORMONE LIVER OVARY INSULIN SHBG IGFBP-1 IGF-1 SEXSTEROIDSYNTHESIS SEXUALMATURATION SOMATIC GROWTH